As a part of our efforts to design prodrugs for antiviral nucleosides, 9-(beta-D-arabinofuranosyl)-6-azidopurine (6-AAP) was synthesized as a prodrug for ara-A that utilizes the azide reduction biotransformation pathway. 6-AAP was synthesized from ara-A via its 6-chloro analogue 4. The bioconversion of the prodrug was investigated in vitro and in vivo, and the pharmacokinetic parameters were determined. For in vitro studies, 6-AAP was incubated in mouse serum and liver and brain homogenates. The half-lives of 6-AAP in serum and liver and brain homogenates were 3.73, 4.90, and 7.29 h, respectively. 6-AAP was metabolized primarily in the liver homogenate microsomal fraction by the reduction of the azido moiety to the amine, yielding ara-A. However, 6-AAP was found to be stable to adenosine deaminase in a separate in vitro study. The in vivo metabolism and disposition of ara-A and 6-AAP were conducted in mice. When 6-AAP was administered by either oral or intravenous route,the half-life of ara-A was 7-14 times higher than for ara-A administered intravenously. Ara-A could not be found in the brain after the intravenous administration of ara-A. However, after 6-AAP administration (by either oral or intravenous route), significant levels of ara-A were found in the brain. The results of this study demonstrate that 6-AAP is converted to ara-A, potentially increasing the half-life and the brain delivery of ara-A. Further studies to utilize the azide reduction approach on other clinically useful agents containing an amino group are in progress in our laboratories.
In an effort to improve the pharmacokinetic properties and tissue distribution of 2'-F-ara-ddI, two lipophilic prodrugs, 6-azido-2'-3'-dideoxy-2'-fluoro-beta-D- arabinofuranosylpurine (FAAddP, 4) and N6-methyl-2'-3'-dideoxy-2'-fluoro-beta-D-arabinofuranosyladenine (FMAddA, 5), were synthesized and their biotransformation was investigated in vitro and in vivo, in mice. Compounds 4 and 5 were synthesized via the intermediate 2. For the in vitro studies, FAAddP and FMAddA were incubated in mouse serum, liver homogenate, and brain homogenate. FAAddP was metabolized in liver homogenate by the reduction of the azido to the amino moiety followed by deamination, yielding 2'-F-ara-ddI. The conversion of FAAddP to 2'-F-ara-ddA was mediated by microsomal P-450 NADPH reductase system, as shown by the liver microsomal assay. FAAddP was also converted to 2'-F-ara-ddI at a slower rate in the brain than in the liver. FMAddA, however, was stable in brain homogenate and was slowly metabolized in the liver homogenate. Metabolic conversion of FMAddA in vitro was stimulated by the addition of adenosine deaminase. In the in vivo metabolism study, FAAddP underwent reduction to 2'-F-ara-ddA followed by deamination to 2'-F-ara-ddI. FMAddA did not result in increased brain delivery of 2'-F-ara-ddI in vivo, probably due to the slow conversion as observed in the in vitro studies. However, there was an increase in the half-life of 2'-F-ara-ddI produced from FMAddA. This report is the first example in the design of prodrugs using the azido group for adenine- and hypoxanthine-containing nucleosides. This interesting and novel approach can be extended to other antiviral and anticancer nucleosides.
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